Cyclophosphamide and Rabbit Antithymocyte Globulin (rATG)/Rituximab in Patients With Systemic Lupus Erythematosus

• ClinicalTrials.gov Identifier: NCT00278538
• Recruitment Status: Completed
• First Posted: January 18, 2006
• Results First Posted: February 28, 2020
• Last Update Posted: February 28, 2020
• Sponsor: Northwestern University
• Information provided by (Responsible Party): Richard Burt, MD, Northwestern University

Tracking Information

• First Submitted Date: January 15, 2006
• First Posted Date: January 18, 2006
• Results First Submitted Date: November 18, 2019
• Results First Posted Date: February 28, 2020
• Last Update Posted Date: February 28, 2020
• Actual Study Start Date: September 23, 2005
• Actual Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: February 17, 2020)

Survival [ Time Frame: 6 months, then yearly x 5 years after transplant ]

The primary efficacy outcome is overall survival.

• Original Primary Outcome Measures (submitted: January 15, 2006): The primary efficacy outcome is overall survival and the proportion of participants who achieve and maintain remission after transplant. Remission is defined according to the RIFLE as duration on no immune suppressive medications except physiologic doses
• Current Secondary Outcome Measures: Not Provided
• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Cyclophosphamide and Rabbit Antithymocyte Globulin (rATG)/Rituximab in Patients With Systemic Lupus Erythematosus
• Official Title: Cyclophosphamide and rATG/Rituximab in Patients With Systemic Lupus Erythematosus: Phase II Trial
• Brief Summary: This study is designed to examine whether treating patients with lupus with high dose cyclophosphamide together with rATG/rituximab (drugs which reduce the function of the immune system), followed by return of their previously collected stem cells will result in improvement in the disease. Stem cells are undeveloped cells that have the capacity to grow into mature blood cells, which normally circulate in the blood stream. The purpose of the intense chemotherapy is to destroy the cells in the immune system which may be causing this disease. The purpose of the stem cell infusion is to produce a normal immune system that will no longer attack body. The study purpose is to examine whether this treatment will result in improvement in the lupus disease.

Detailed Description

Mobilization Participants will be administered Cyclophosphamide at 2.0 g/m2 in 200 ml of normal saline (NS) over 1 hour. Hydration with 0.9 NS at approximately 100-250-ml/ hour will begin 4 hours prior to cyclophosphamide and continued for 24 hours after termination of cyclophosphamide. Urine output approximately greater than 100 ml/hour should be maintained.

Granulocyte-colony stimulating factor (G-CSF) will be administered subcutaneously at 5-10 mcg/kg/day and will be started 5 days after termination of cyclophosphamide administration.

After the absolute neutrophil count is greater than 1000/ul or after hematological nadir, leukapheresis using a continuous flow blood cell separator will be initiated. A 10-15 liter apheresis will be performed unless stopped earlier for clinical judgment of toxicity (e.g., numbness, tetany). The G-CSF will continue until apheresis is discontinued. If necessary, platelets will be transfused to greater than 60,000/ul prior to each apheresis.

Conditioning Regimen Mesna: 50mg/kg/day x 4 days will be given intravenously over 24 hours.

Cyclophosphamide: 50 mg/kg/day x 4 days (the lesser of ideal or actual weight) will be given intravenously over 1 hour in 250 cc of normal saline on days -5 through -2.

Hydration: approximately 50-200cc/hour in adults should begin 6 hours before cyclophosphamide and continue until 24 hours after the last cyclophosphamide dose. Hydration rates need to be individually adjusted by daily weights to maintain dry weight count. Twice daily weights will be obtained. Warning: Participants with renal insufficiency are prone to volume overload. Early institution of ultrafiltration or dialysis is recommended.

rATG 0.5mg/kg will be given IV on day -5, 1.0mg/kg will be given on day

-4, 1.5mg/kg will be given IV on days -3, -2, -1 (no dose adjustment). It will be given over 10 hours. Premedicate with Solumedrol 250mg IV, acetaminophen 650mg po qd and diphenhydramine 25mg 30 minutes before infusion.

Rituximab 500mg/day will be given IV on days -6 and +1. At the first dose (D-6), rituximab infusion will be started at 50mg/h and escalate the infusion rate by 50mg every 30minutes to a maximum of 400mg/h. Starting the second dose (days -4, -2 and +1). IV infusion will be started at 100mg/h and escalate the infusion rate 100mg every 30minutes to a maximum of 400mg/h. Premedicate with Solumedrol 250mg IV, acetaminophen 650mg po qd and diphenhydramine 25mg 30 minutes before infusion on days -6 and +1. Premedicate acetaminophen 650mg po qd and diphenhydramine 25mg 30 minutes before infusion on days -4 and -2.

Stem Cell Reinfusion Previously collected stem cells will be reinfused on day 0 as noted in Table 4. The stem cells are infused over approximately 20 minutes through the central venous catheter, such as a peripherally inserted central catheter (PICC line). Following stem cell reinfusion, routine daily labs will be obtained including complete blood count (CBC), chemistry panel, and liver function tests. Antibiotics and blood transfusions will be administered as required by clinical judgment.

• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Systemic Lupus Erythematosus

Intervention

Biological: Hematopoietic stem cell transplantation

Autologous hematopoietic stem cell transplantation

Study Arms

Experimental: Hematopoietic Stem Cell Transplant Regimen 2

Autologous Hematopoietic Stem Cell Transplantation: Rituximab, rATG and Cyclophosphamide regimen

Intervention: Biological: Hematopoietic stem cell transplantation

Publications *

• Burt RK, Han X, Gozdziak P, Yaung K, Morgan A, Clendenan AM, Henry J, Calvario MA, Datta SK, Helenowski I, Schroeder J. Five year follow-up after autologous peripheral blood hematopoietic stem cell transplantation for refractory, chronic, corticosteroid-dependent systemic lupus erythematosus: effect of conditioning regimen on outcome. Bone Marrow Transplant. 2018 Jun;53(6):692-700. doi: 10.1038/s41409-018-0173-x. Epub 2018 May 31.
• Burt RK, Craig RM, Milanetti F, Quigley K, Gozdziak P, Bucha J, Testori A, Halverson A, Verda L, de Villiers WJ, Jovanovic B, Oyama Y. Autologous nonmyeloablative hematopoietic stem cell transplantation in patients with severe anti-TNF refractory Crohn disease: long-term follow-up. Blood. 2010 Dec 23;116(26):6123-32. doi: 10.1182/blood-2010-06-292391. Epub 2010 Sep 13.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: February 17, 2020): 32
• Original Enrollment (submitted: January 15, 2006): 20
• Actual Study Completion Date: May 2019
• Actual Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Ages 15 to 60 years old
• Meet at least 4 of 11 American College of Rheumatology (ACR) Classification criteria for systemic lupus erythematosus (SLE) (see Appendix 16.2)

• Meet one of following five:

  1. For lupus nephritis, participants must fail pulse cyclophosphamide (500 to 1000 mg/m2 monthly for a minimum of 6 months). Failure is defined as meeting criteria to be considered as BILAG renal category A.
  2. For visceral organ involvement other than nephritis, participants must be BILAG cardiovascular/respiratory category A, vasculitis category A, or neurologic category A and must fail at least 3 months of oral or IV cyclophosphamide and be corticosteroid dependent. Steroid dependence being defined as at least 3 months of steroid therapy and inability to wean corticosteroid to less than 20 mg/day of prednisone or equivalent.
  3. For cytopenias that are immune mediated, participants must be BILAG hematologic category A. Participants must fail corticosteroids (either oral prednisone > 0.5 mg/kg/day for more than 6 months or pulse methylprednisolone for at least one cycle of three days), and at least one of the following: azathioprine at 2 mg/kg/day for at least 3 months, mycophenolate mofetil 2 grams daily for more than 3 months, cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine at least 3 mg/kg/day for at least 3 months, danazol for at least 3 months, or splenectomy.
  4. For mucocutaneous disease, participants must meet BILAG mucocutaneous category A, be unable to be weaned from prednisone to less than 0.5 mg/kg/day for more than 6 months and obvious cushingoid habitus, and have received at least one of the following: azathioprine at 2 mg/kg/day for at least 3 months, methotrexate at 15mg/week for at least 3 months, cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine at least 3 mg/kg/day for at least 3 months.
  5. For arthritis/myositis, participants must meet BILAG musculoskeletal category A, be unable to be weaned from prednisone to less than 0.5 mg/kg/day for more than 6 months and obvious cushingoid habitus, and have received at least one of the following: azathioprine at 2 mg/kg/day for at least 3 months, methotrexate at 15mg/ week for at least 3 months, cyclophosphamide intravenously or orally for at least 3 months, or cyclosporine at least 3 mg/kg/day for at least 3 months.
• Able to give informed consent.
• If indication for hematopoietic stem cell transplant (HSCT) is nephritis, a renal biopsy must demonstrate the potential of a reversible (non-fibrotic) component indicating that if successful the participant would not be likely to be permanently dialysis-dependent after transplant.
• Since the BILAG is only one of multiple indices for SLE, patients may also be candidates if despite prior immune suppression therapy as described above, patients are still on active immune suppression (more than 10mg a day of prednisone).
• Patients with SLE whose major manifestation is Antiphospholipid syndrome (APS) may be candidates without prior immune suppression therapy if they have had a visceral organ thrombotic or embolic event despite anticoagulation.
• Patients with SLE whose major manifestation is Antiphospholipid syndrome (APS) may be candidates without prior immune suppression therapy if they have had a visceral organ thrombotic or embolic event despite anticoagulation.

Exclusion Criteria:

• HIV positive
• Ongoing malignancy except localized basal cell or squamous skin cancer. Other malignancies for which the participant is judged to be cured by local surgical therapy, such as head and neck cancer, or stage I or II breast cancer will be considered on an individual basis by the investigators doing the final screening for participant qualification.
• Positive pregnancy test, inability or unwillingness to pursue effective means of birth control, failure to willingly accept or comprehend irreversible sterility as a side effect of therapy.
• Psychiatric illness or mental deficiency making compliance with treatment or informed consent impossible.
• Diffusing capacity of lung for carbon monoxide (DLCO) < 45% of predicted unless attributed to active lupus.
• Resting left ventricular ejection fraction (LVEF) < 40% unless attributed to active lupus.
• Known hypersensitivity to E Coli derived proteins.
• Transaminases greater than 2 times normal unless attributed to active lupus.
• Positive tuberculosis skin test
• Any active infection
• Any co-morbid illness that in the opinion of the investigator would jeopardize the ability of the subject to tolerate the study.
• Failure to collect at least 2.0 x 106 cluster of differentiation 34 (CD34+) cells/kg
• Antinuclear antibody (ANA)-negative

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 15 Years to 60 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT00278538
• Other Study ID Numbers: DI SLE.Auto2003
• Has Data Monitoring Committee: Yes
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Richard Burt, MD, Northwestern University
• Original Responsible Party: Not Provided
• Current Study Sponsor: Northwestern University
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Richard Burt, MD; Northwestern University

• PRS Account: Northwestern University
• Verification Date: November 2019